Radiotherapy augments the immune response to prostate cancer in a time‐dependent manner

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Abstract
BACKGROUND Cancer immunotherapy refers to an array of strategies intended to treat progressive tumors by augmenting a patient's anti‐tumor immune response. As immunotherapy is eventually incorporated into oncology treatment paradigms, it is important to understand how these therapies interact with established cancer treatments such as chemotherapy or Radiotherapy (RT). To address this, we utilized a well‐established, autochthonous murine model of prostate cancer to test whether RT could augment (or diminish) the CD4 T cell response to a tumor vaccine. METHODS Transgenic mice that develop spontaneous prostate cancer (TRAMP) which also express a unique tumor associated antigen (Influenza hemagglutinin) under the control of a prostate‐specific promoter were given local RT in combination with immunotherapy. The immunological outcome of this combinatorial strategy was assayed by monitoring the effector response of adoptively transferred, prostate‐specific CD4 T cells. RESULTS Neither RT nor immunotherapy alone was capable of priming an anti‐tumor immune response in animals with evolving tumors. The combination of immunotherapy with RT resulted in anti‐tumor T cell activation—this effect was profoundly dependent on the relative timing of RT and immunotherapy. Anti‐tumor immune responses occurred when immunotherapy was administered 3–5 weeks post‐RT, but such responses were undetectable when immunotherapy was administered either earlier (peri‐radiothrerapy) or later. CONCLUSIONS The therapeutic temporal window of immunotherapy post‐RT suggests that highly aggressive, immuno‐suppressive tumors might be most sensitive to immunotherapy in a fairly narrow time window; these results should help to guide future development of clinical combinatorial strategies. Prostate 68:1319–1329, 2008.